Project Summary Myc oncoprotein is known to drive reprogramming of energy metabolism to meet the needs of energy consumption, macromolecule biosynthesis, and waste disposal in cancer cells. Cancers with elevated level of Myc exhibit an increased dependency on glutamine, which has been attributed to glutaminase (GLS), the enzyme catalyzing the deamination of glutamine into glutamate to fuel the tricarboxylic acid (TCA) cycle. Intriguingly, my sponsor Dr. Wei-Xing Zong's laboratory recently found that Myc can induce the expression of glutamine synthetase (GS), the enzyme that catalyzes the reverse reaction of GLS, to promote the de novo synthesis of glutamine from glutamate and ammonia. My preliminary data demonstrate that ectopic GS expression leads to elevated glutamine that is used for nucleotide synthesis, uptake of essential amino acids, increased cell growth/proliferation/survival, and tumorigenesis. These data prompt the formation of the hypothesis that GS is a critical mediator of Myc-driven tumorigenesis by generating glutamine to meet the increased demand of glutamine in cancer cells. Two specific aims are proposed to test this hypothesis: 1) Study the effect of GS on glutamine metabolism and oncogenesis in the context of Myc activation; and 2) Study how Myc differentially regulates GS and GLS and how these two enzymes regulate cell metabolism and tumorigenesis in a context-dependent manner. Accomplishment of this project will unravel a novel mechanism through which Myc promotes reprogramming of cancer cell metabolism, and will help to establish GS as a therapeutic target. This study will also offer a unique opportunity for me to receive top-notch training in both oncogenic signaling and in cancer cell metabolism, which will largely help me to achieve my career goal to become an independent cancer biologist.